Methods comprising continuous administration of a GLP-1 receptor agonist and co-administration of a drug

ABSTRACT

Provided is a method for administering to a subject, via an implantable delivery device, a continuous subcutaneous dose of glucagon-like peptide-1 (GLP-1) analog, where the subject is orally co-administered a drug after implantation of the implantable delivery device and during continuous subcutaneous dosing of the GLP-1 analog.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims priority to and the benefit of U.S. ProvisionalApplication Ser. 62/441,833, filed Jan. 3, 2017, which is hereinincorporated by reference in its entirety.

SEQUENCE LISTING

The instant application contains a Sequence Listing which has beensubmitted in ASCII format via EFS-Web and is hereby incorporated byreference in its entirety. Said ASCII copy, created on Jan. 2, 2018 isnamed ITCA-052-001US ST25.txt and is 743 bytes in size.

BACKGROUND

By some estimates, over 350 million people worldwide are presentlydiagnosed with type 2 diabetes mellitus (T2D) and one in three people inthe United States will develop T2D in their lifetime. For treatment ofthis disease, the American Diabetes Association (ADA) recommendsmetformin as first-line therapy due to its low cost, availability andreasonable efficacy in reducing glycated hemoglobin (HbA1c), despitecertain shortcomings associated with this drug. The ADA also recommendspotential second-line options, including glucagon-like peptide-1 (GLP-1)receptor agonists, sodium-glucose cotransporter 2 (SGLT2) inhibitors,dipeptidyl peptidase-4 inhibitors (DPP-4), sulfonylureas,thiazolidinediones and insulin. Treatment of T2D with GLP-1 receptoragonist peptides, in particular, has grown. GLP-1 receptor agonistsgenerally provide important effects in subjects beyond blood glucosecontrol, such as effecting weight loss, preserving beta-cell function,and mitigating hypertension, hypoglycemia and/or hyperlipidemia. Methodsare presently needed to more fully and properly implement treatment withGLP-1 receptor agonists and better address growing needs of subjectswith T2D, obesity or excessive body weight, some of whom mustsimultaneously manage treatment of unrelated diseases or disorders.

SUMMARY

Periodic and subcutaneous administrations (i.e., injections) of a GLP-1receptor agonist are presently used to achieve a glucose-dependentincrease in insulin in subjects with T2D. The present inventionencompasses the recognition of a problem regarding treatment of T2D withGLP-1 receptor agonists. Specifically, injections of certain GLP-1receptor agonists generally slow gastric emptying and can reduce theextent and rate of absorption of orally administered drugs. Uponinjection of certain GLP-1 receptor agonists, co-administration ofcertain drugs for treatment of diseases other than T2D may require doseadjustment of these drugs (relative to doses prescribed for the drugswhen administered alone) or preclude co-administration of certain drugsupon injection of the GLP-1 receptor agonists. Certain injectable GLP-1receptor agonists have been found to distort areas under the curve(AUC), C_(max), and T_(max) for certain orally available drugs fortreatment of diseases, disorders or conditions unrelated to T2D uponco-administration. Consequently, since doses adjustments are oftenimpractical, such drugs must be administered before (e.g., at least onehour prior to) injection of the GLP-1 receptor agonist.

For example, according to prescribing information (PI) for injectableByetta® (exenatide) for the treatment of T2D, “[oral contraceptive] OCproducts should be administered at least one hour prior to BYETTAinjection.” As explained in the PI for Byetta®, co-administration of anoral contraceptive and Byetta® results in decreased C_(max) and delayedT_(max) for the oral contraceptive: “The effect of BYETTA (10 mcg BID)on single and on multiple doses of a combination oral contraceptive (35mcg ethinyl estradiol plus 150 mcg levonorgestrel) was studied inhealthy female subjects. Repeated daily doses of the oral contraceptive(OC) given 30 minutes after BYETTA administration decreased the C_(max)of ethinyl estradiol and levonorgestrel by 45% and 27%, respectively anddelayed the T_(max) of ethinyl estradiol and levonorgestrel by 3.0 hoursand 3.5 hours, respectively, as compared to the oral contraceptiveadministered alone. Administration of repeated daily doses of the OC onehour prior to BYETTA administration decreased the mean C_(max) ofethinyl estradiol by 15% but the mean C_(max) of levonorgestrel was notsignificantly changed as compared to when the OC was given alone.”

Also according to prescribing information (PI) for injectable Byetta®(exenatide) for the treatment of T2D, “[a]cetaminophen AUC, C_(max) andT_(max) were not significantly changed when acetaminophen was given 1hour before BYETTA injection.” However, a s explained in the PI forByetta®, co-administration of a pain reliever such as acetaminophen withByetta® or after Byetta® injection, results in decreased areas under thecurve (AUC) and C_(max), and increases in T_(max), for acetaminophen.“When 1000 mg acetaminophen elixir was given with 10 mcg BYETTA (0 h)and 1 hour, 2 hours, and 4 hours after BYETTA injection, acetaminophenAUCs were decreased by 21%, 23%, 24%, and 14%, respectively; C_(max) wasdecreased by 37%, 56%, 54%, and 41%, respectively; T_(max) was increased[delayed] from 0.6 hour in the control period to 0.9 hour, 4.2 hours,3.3 hours, and 1.6 hours, respectively.”

Unfortunately, real life circumstances often preclude subjects (i.e.,human subjects) from adhering to prescribing information regardingpre-administration of drugs for treatment(s) unrelated to T2D prior toinjection of a GLP-1 receptor agonist for the treatment of T2D. GLP-1receptor agonists include twice-daily injectable Byetta® (exenatide),once-daily injectable Victoza® (liraglutide), once weekly injectableTrulicity® (dulaglutide) and once weekly injectable Ozempic®(semaglutide). Specifically, real life onset of conditions such as pain,heart attack, hypertension, stroke, blood clot, or the need forcontraception commonly occur after, sometimes immediately after, bolusinjection of a GLP-1 receptor agonist. Yet, when confronted with suchcircumstances, the subject must delay treatment until one or severalhours before administration of the next injection of GLP-1 receptoragonist. Failure to adhere to this prescribing information, as itrelates to pre-administration of such drugs before bolus injection ofthe GLP-1 receptor agonist, puts subjects at risk of effectingsuboptimal AUC, C_(max) and/or T_(max) of such drugs.

It has been discovered that continuous administration of GLP-1 receptoragonists, such as exenatide, via an implantable delivery device is notaccompanied by either substantial delays in gastric emptying (See FIGS.1 & 2) or substantial reductions in blood concentrations of glucagon(See FIGS. 3-5). Without being bound by theory, it thus appears thatdelays in gastric emptying and reductions in blood concentrations ofglucagon are substantially attributable to the mode of administrationfor certain GLP-1 receptor agonists.

It has also been discovered that certain drugs other than those fortreating T2D (e.g., drugs for treatment or prevention of pain,conditions associated with heart disease or a heart attack,hypertension, stroke or blood clot, and oral contraceptives) caneffectively be co-administered upon continuous administration of a GLP-1receptor agonist via an implantable delivery device. Therefore, therequirement for pre-administration of certain drugs, relative toinjection of the GLP-1 receptor agonist such as exenatide, similarlyappear attributable to the mode of administration for the GLP-1 receptoragonist.

Thus, whereas bolus injection of a GLP-1 receptor agonist such asByetta® require advance oral administration of certain drugs (e.g., fortreatment or prevention of pain and oral contraceptives) at least onehour prior to injection of Byetta®, applicants have discovered that suchdrugs can be orally administered after implantation of an osmoticdelivery device and during continuous subcutaneous delivery (e.g.,during three, six, twelve, or twenty-four month administration periods)of a GLP-1 analog such as exenatide (e.g., at 20 μg/day or 60 μg/dayITCA-650). This increased versatility of co-administration providessubjects, who have been administered implantable osmotic deliverydevices for continuous subcutaneous delivery of a GLP-1 analog, with theoption to effectively co-administer orally available drugs (e.g., fortreatment of pain, a heart condition, heart attack, hypertension,stroke, and/or preventing a blood clot or providing contraception) atany time during three, six, twelve, or twenty-four month administrationperiod of continuous subcutaneous delivery of the GLP-1 analog.

In certain embodiments, the present invention provides a method foradministering to a subject, via an implantable delivery device, acontinuous subcutaneous dose of glucagon-like peptide-1 (GLP-1) analog,where the subject is orally co-administered a drug after implantation ofthe implantable delivery device and during continuous subcutaneousdosing of the GLP-1 analog. In other words, the subject isco-administered the drug following implantation of the implantabledelivery device and during three, six, twelve, or twenty-four monthadministration period of continuous subcutaneous delivery of the GLP-1analog without resorting to advance administration of the drug prior toadministration (i.e., implantation) of the GLP-1 analog.

Although methods and materials similar or equivalent to those describedherein can be used in the practice or testing of the present invention,suitable methods and materials are described below. All publications,patent applications, patents, and other references mentioned herein areincorporated by reference in their entirety. The references cited hereinare not admitted to be prior art to the claimed invention. In the caseof conflict, the present Specification, including definitions, willcontrol. In addition, the materials, methods, and examples areillustrative only and are not intended to be limiting. Other featuresand advantages of the invention will be apparent from the followingdetailed description and claims.

BRIEF DESCRIPTIONS OF THE DRAWINGS

The above and further features will be more clearly appreciated in viewof the following detailed description and accompanying drawings.

FIG. 1 is a graph illustrating 0-30-minute increments in plasma glucoselevels during test meals for 10-, 20-, 40- and 80 μg/day exenatidetreatments, measured before and after 5, 15, and 29 days of treatment.Symbols are group means of individual increments±standard error of themean (SEM).

FIG. 2 is a graph illustrating dose-responses for 30-minute changes inglucose concentrations during test meals relative to pre-treatmentvalues. Curves for Days 5, 15 and 29 are 3-parameter sigmoidsconstrained to share a common effective dose causing 50% inhibition(ED₅₀). Symbols are group means of individual values±SEM.

FIG. 3 depicts graphs illustrating plasma glucagon profiles during mealtolerance tests plotted according to duration of treatment (differentsymbols and colors) for each of the 4 dose groups (separate panels).Symbols are means±SEM for data present at each condition.

FIG. 4 depicts graphs illustrating changes in plasma glucagonconcentration from pre-meal values during a test meal. Symbols, colorsand layout have the same meanings as those in FIG. 3.

FIG. 5 depicts graphs illustrating integrated glucagon concentrations(left panel) or glucagon changes (right panel) during Meal ToleranceTest (MTT) as a function of duration of treatment for each dose group.

FIG. 6A (left), redrawn from Saad et al., is a graph illustratingchanging [insulin] vs [glucose] relationship during the progression fromnormal glucose tolerance to T2D.

FIG. 6B (right) is a graph that exemplifies the diverse [insulin] vs[glucose] relationships in the current study.

FIG. 7 is a graph illustrating multiples above pre-treatment baseline ofbest fitting [insulin]×[glucose] slopes. The curves are the best fittingexponential association as a function of duration of treatment.

FIG. 8 is a graph illustrating dose response for the effect of ITCA-650to increase slope of the [insulin]/[glucose] relationship.

FIG. 9 is a graph illustrating mean plasma concentrations ofacetaminophen over time, at day 27, alone and upon co-administrationwith ITCA-650, during continuous delivery of exenatide via an implantedosmotic delivery device.

FIG. 10 provides statistical assessments of drug-drug interactions ofexenatide and ethinyl estradiol (EE) and levonorgestrel (LNG) fromLevora® (OC) during continuous delivery of exenatide via an implantedosmotic delivery device.

FIG. 11 is a chart that illustrates pharmacokinetic parametersdemonstrating that ITCA-650 did not substantially affectpharmacokinetics of certain orally co-administered medications to aclinically relevant degree.

DETAILED DESCRIPTION Definitions

Glucagon-like peptide-1 (GLP-1) derives from pre-proglucagon, a 158amino acid precursor polypeptide that is processed in different tissuesto form a number of different proglucagon-derived peptides, includingglucagon, glucagon-like peptide-1 (GLP-1), glucagon-like peptide-2(GLP-2) and oxyntomodulin (OXM), that are involved in a wide variety ofphysiological functions, including glucose homeostasis, insulinsecretion, gastric emptying, and intestinal growth, as well as theregulation of food intake. GLP-1 is produced as a 37-amino acid peptidethat corresponds to amino acids 72 through 108 of proglucagon (92 to 128of preproglucagon). GLP-1(7-36) amide or GLP-1(7-37) acid arebiologically active forms of GLP-1, that demonstrate essentiallyequivalent activity at the GLP-1 receptor.

GLP-1 and GLP-1 analogs, acting as agonists at the GLP-1 receptor, havebeen shown to provide effective hypoglycemic control, e.g., for treatingpatients with type-2 diabetes. Certain GLP-1 analogs are being sold orare in development for treatment of type-2 diabetes including, e.g.,Byetta® & Bydureon BCise® (exenatide), Ozempic® (semaglutide), Victoza®(liraglutide), Adlyxin® (lixisenatide); Tanzeum® (albiglutide), andTrulicity® (dulaglutide).

The term “osmotic delivery device” as used herein typically refers to adevice used for delivery of a drug (e.g., an insulinotrophic peptide) toa subject, wherein the device comprises, for example, a reservoir (made,e.g., from a titanium alloy) having a lumen that contains a suspensionformulation comprising a drug (e.g., an insulinotrophic peptide) and anosmotic agent formulation. A piston assembly positioned in the lumenisolates the suspension formulation from the osmotic agent formulation.A semi-permeable membrane is positioned at a first distal end of thereservoir adjacent the osmotic agent formulation and a diffusionmoderator (which defines a delivery orifice through which the suspensionformulation exits the device) is positioned at a second distal end ofthe reservoir adjacent the suspension formulation. Typically, theosmotic delivery device is implanted within the subject, for example,subdermally or subcutaneously (e.g., in the abdominal area or in theinside, outside, or back of the upper arm). An exemplary osmoticdelivery device is the DUROS® delivery device. Examples of termssynonymous to “osmotic delivery device” include but are not limited to“osmotic drug delivery device,” “osmotic drug delivery system,” “osmoticdevice,” “osmotic delivery device,” “osmotic delivery system,” “osmoticpump,” “implantable drug delivery device,” “drug delivery system,” “drugdelivery device,” “implantable osmotic pump,” “implantable drug deliverysystem,” and “implantable delivery system.” Other terms for “osmoticdelivery device” are known in the art. As used herein, “ITCA 650” is anosmotic delivery device comprising exenatide having the amino acidsequence of SEQ ID NO: 1:H-His-Gly-Glu-Gly-Thr-Phe-Thr-Ser-Asp-Leu-Ser-Lys-Gln-Met-Glu-Glu-Glu-Ala-Val-Arg-Leu-Phe-Ile-Glu-Trp-Leu-Lys-Asn-Gly-Gly-Pro-Ser-Ser-Gly-Ala-Pro-Pro-Pro-Ser-NH₂.

The term “continuous delivery” as used herein typically refers to asubstantially continuous release of drug from an osmotic delivery deviceand into tissues near the implantation site, e.g., subdermal andsubcutaneous tissues. For example, the osmotic delivery device releasesdrug essentially at a predetermined rate based on the principle ofosmosis. Extracellular fluid enters the osmotic device through thesemi-permeable membrane directly into the osmotic engine that expands todrive the piston at a slow and consistent rate of travel. Movement ofthe piston forces the drug formulation to be released through theorifice of the diffusion moderator. Thus, release of the drug from theosmotic delivery device is at a slow, controlled, consistent rate.

The term “substantial steady-state delivery” as used herein typicallyrefers to delivery of a drug at or near a target concentration over adefined period of time, wherein the amount of the drug being deliveredfrom an osmotic delivery device is substantially zero-order delivery.Substantial zero-order delivery of a therapeutic agent (e.g., aninsulinotrophic peptide, preferably, an exenatide) means that the rateof drug delivered is constant and is independent of the drug availablein the delivery system; for example, for zero-order delivery, if therate of drug delivered is graphed against time and a line is fitted tothe data the line has a slope of approximately zero, as determined bystandard methods (e.g., linear regression).

As used herein, the terms “treatment,” “treat,” and “treating” refer toreversing, alleviating, ameliorating, delaying the onset of, orinhibiting the progress of a disease or disorder, or one or moresymptoms thereof, as described herein. In some embodiments, treatmentmay be administered after one or more symptoms have developed. In otherembodiments, treatment may be administered in the absence of symptoms.For example, treatment may be administered to a susceptible individualprior to the onset of symptoms (e.g., in light of a history of symptomsand/or in light of genetic or other susceptibility factors). Treatmentmay also be continued after symptoms have resolved, for example toprevent or delay their recurrence.

The term “subject,” as used herein, means an animal, preferably amammal, and most preferably a human. The term “subject,” as used herein,also means a patient, preferably a human patient suffering from T2D,obesity or in need of weight loss.

As used herein, the term “co-administration” generally refers toseparate administration of a drug to a subject during or after bolusinjection of GLP-1 receptor agonist to the subject, or separateadministration of a drug to a subject during or after insertion in thesubject of an osmotic delivery device comprising GLP-1 receptor agonistsuch as exenatide.

The term “dose adjustment” refers to a change in dosage of a drug fortreatment of a disease or disorder other than type-2 diabetes that ismade upon co-administration of a GLP-1 receptor agonist, relative to thedosage used upon administration of the drug alone or in the absence ofthe GLP-1 receptor agonist.

Unless otherwise defined, all technical and scientific terms used hereinhave the same meaning as commonly understood by one of ordinary skill inthe art to which this invention belongs. In the Specification, thesingular forms also include the plural unless the context clearlydictates otherwise; as examples, the terms “a,” “an,” and “the” areunderstood to be singular or plural and the term “or” is understood tobe inclusive. By way of example, “an element” means one or more element.Throughout the specification the word “comprising,” or variations suchas “comprises” or “comprising,” will be understood to imply theinclusion of a stated element, integer or step, or group of elements,integers or steps, but not the exclusion of any other element, integeror step, or group of elements, integers or steps. About can beunderstood as within 10%, 9%, 8%, 7%, 6%, 5%, 4%, 3%, 2%, 1%, 0.5%,0.1%, 0.05%, or 0.01% of the stated value. Unless otherwise clear fromthe context, all numerical values provided herein are modified by theterm “about.”

DESCRIPTION OF EXEMPLARY EMBODIMENTS

In one aspect, the present invention provides a method comprisingadministering to a subject, via an implantable delivery device, acontinuous subcutaneous dose of glucagon-like peptide-1 (GLP-1) analog,where the subject is orally co-administered a drug after implantation ofthe implantable delivery device and during continuous subcutaneousdosing of the GLP-1 analog.

In another aspect, the present invention provides a drug for use in amethod of treatment of a subject (e.g., a patient suffering from T2Dand/or obesity and/or in need of weight loss), the method comprisingadministering to the subject (e.g., patient), via an implantable osmoticdelivery device, a continuous subcutaneous dose of a glucagon-likepeptide-1 (GLP-1) analog; and orally co-administering a drug afterimplantation of the implantable delivery device and during continuoussubcutaneous dosing of the GLP-1 analog.

In some embodiments, the subject is orally co-administered a drug onehour to six months after implantation of the implantable deliverydevice. In some embodiments, the subject is orally co-administered adrug one hour to twenty-four hours after implantation of the implantabledelivery device. In some embodiments, the subject is orallyco-administered a drug one day to seven days after implantation of theimplantable delivery device. In some embodiments, the subject is orallyco-administered a drug one week to one month after implantation of theimplantable delivery device. In some embodiments, the subject is orallyco-administered a drug one month to three months after implantation ofthe implantable delivery device. In some embodiments, the subject isorally co-administered a drug three months to six months afterimplantation of the implantable delivery device. In some embodiments,the subject is orally co-administered a drug six months to one yearafter implantation of the implantable delivery device. In someembodiments, the subject is orally co-administered a drug one year totwo years after implantation of the implantable delivery device.

In some embodiments, the drug is administered for treatment of a diseaseor disorder other than type-2 diabetes. In some embodiments, the diseaseor disorder other than type-2 diabetes is selected from the groupconsisting of pain, elevated blood levels of cholesterol, heart disease,hypertension, heart attack, stroke or blood clot.

In some embodiments, the drug is a contraceptive administered to preventconception of a child.

In some embodiments, the drug is selected from the group consisting ofacetaminophen, atorvastatin, lisinopril, digoxin, ethinyl estradiol,levonorgestrel, R-warfarin, and/or S-warfarin.

In some embodiments, the drug is a pain reliever, such as acetaminophen.

In some embodiments, the drug is acetaminophen and the ratio of the AUCfor co-administered acetaminophen after implantation of the implantabledelivery device and during continuous subcutaneous dosing of the GLP-1analog relative to reference AUC for acetaminophen administered alone isbetween 1.0 and 1.25 or between 0.75 and 1.25.

In some embodiments, the drug is acetaminophen and the AUC forco-administered acetaminophen (e.g., co-administered within 1, 2 or 4hours of implantation) and during continuous subcutaneous dosing of theGLP-1 analog are reduced less than 10% or 5% relative to reference AUCfor acetaminophen administered alone.

In some embodiments, the drug is acetaminophen and the ratio of theC_(max) for co-administered acetaminophen after implantation of theimplantable delivery device and during continuous subcutaneous dosing ofthe GLP-1 analog relative to reference C_(max) for acetaminophenadministered alone is between 1.0 and 1.25 or between 0.75 and 1.25.

In some embodiments, the drug is acetaminophen and the C_(max) forco-administered acetaminophen (e.g., within 1, 2 or 4 hours ofimplantation) and during continuous subcutaneous dosing of the GLP-1analog are reduced less than 30%, 20%, 10% or 5% relative to referenceC_(max) for acetaminophen administered alone.

In some embodiments, the drug is acetaminophen and the T_(max) forco-administered acetaminophen (e.g., within 1, 2 or 4 hours ofimplantation) and during continuous subcutaneous dosing of the GLP-1analog is increased by less than 2 hours or 1 hour relative to referenceT_(max) for acetaminophen administered alone.

In some embodiments, the drug is an oral contraceptive, such as ethinylestradiol and/or levonorgestrel. In some embodiments, the oralcontraceptive is a combination of ethinyl estradiol and levonorgestrel(e.g., Levora®, 35 mcg ethinyl estradiol plus 150 mcg levonorgestrel).

In some embodiments, the drug is ethinyl estradiol and/or levonorgestreland the ratio of the AUC for co-administered ethinyl estradiol and/orlevonorgestrel after implantation of the implantable delivery device andduring continuous subcutaneous dosing of the GLP-1 analog relative toreference AUC for ethinyl estradiol and/or levonorgestrel administeredalone is between 0.75 and 1.25 or between 0.75 and 1.50.

In some embodiments, the drug is ethinyl estradiol and/or levonorgestreland the ratio of the C_(max) for co-administered ethinyl estradioland/or levonorgestrel after implantation of the implantable deliverydevice and during continuous subcutaneous dosing of the GLP-1 analogrelative to reference C_(max) for ethinyl estradiol and/orlevonorgestrel administered alone is between 0.75 and 1.25 or between0.75 and 1.50.

In some embodiments, the drug is ethinyl estradiol and/or levonorgestreland the C_(max) for co-administered ethinyl estradiol and/orlevonorgestrel (e.g., within 1, 2 or 4 hours of implantation) and duringcontinuous subcutaneous dosing of the GLP-1 analog are reduced less than30%, 20%, 10% or 5% relative to reference C_(max) for ethinyl estradioland/or levonorgestrel administered alone.

In some embodiments, the drug is ethinyl estradiol and/or levonorgestreland the T_(max) for co-administered ethinyl estradiol and/orlevonorgestrel (e.g., within 1, 2 or 4 hours of implantation) and duringcontinuous subcutaneous dosing of the GLP-1 analog is increased lessthan 3 hours, 2 hours or 1 hour relative to reference T_(max) forethinyl estradiol and/or levonorgestrel administered alone.

In some embodiments, the drug is for the treatment or prevention ofelevated blood levels of cholesterol. In some embodiments, the drug is astatin. In some embodiments, the drug is atorvastatin.

In some embodiments, the drug is atorvastatin and the ratio of the AUCfor co-administered atorvastatin after implantation of the implantabledelivery device and during continuous subcutaneous dosing of the GLP-1analog relative to reference AUC for atorvastatin administered alone isbetween 1.0 and 1.25 or between 1.0 and 1.50.

In some embodiments, the drug is atorvastatin and the ratio of theC_(max) for co-administered atorvastatin after implantation of theimplantable delivery device and during continuous subcutaneous dosing ofthe GLP-1 analog relative to reference C_(max) for atorvastatinadministered alone is between 1.0 and 1.5 or between 1.0 and 1.75.

In some embodiments, the drug is for the treatment or prevention ofhypertension and/or heart disease. In some embodiments, the drug isdigoxin.

In some embodiments, the drug is digoxin and the ratio of the AUC forco-administered digoxin after implantation of the implantable deliverydevice and during continuous subcutaneous dosing of the GLP-1 analogrelative to reference AUC for digoxin administered alone is between 1.0and 1.25 or between 1.0 and 1.50.

In some embodiments, the drug is digoxin and the ratio of the C_(max)for co-administered digoxin after implantation of the implantabledelivery device and during continuous subcutaneous dosing of the GLP-1analog relative to reference C_(max) for digoxin administered alone isbetween 1.0 and 1.25 or between 1.0 and 1.50.

In some embodiments, the drug is an angiotensin converting enzyme (ACE)inhibitor. In some embodiments, the drug is lisinopril.

In some embodiments, the drug is lisinopril and the ratio of the AUC forco-administered lisinopril after implantation of the implantabledelivery device and during continuous subcutaneous dosing of the GLP-1analog relative to reference AUC for lisinopril administered alone isbetween 1.5 and 2.0 or between 1.0 and 2.0.

In some embodiments, the drug is lisinopril and the ratio of the C_(max)for co-administered lisinopril after implantation of the implantabledelivery device and during continuous subcutaneous dosing of the GLP-1analog relative to reference C_(max) for lisinopril administered aloneis between 1.25 and 1.75 or between 1.0 and 2.0.

In some embodiments, the drug is for the treatment or prevention of aheart attack, stroke, and/or blood clot. In some embodiments, the drugis an anticoagulant. In some embodiments, the drug is R-warfarin and/orS-warfarin.

In some embodiments, the drug is R-warfarin and/or S-warfarin and theratio of the AUC for co-administered R-warfarin and/or S-warfarin afterimplantation of the implantable delivery device and during continuoussubcutaneous dosing of the GLP-1 analog relative to reference AUC forR-warfarin and/or S-warfarin administered alone is between 1.0 and 1.25or between 0.75 and 1.5.

In some embodiments, the drug is R-warfarin and/or S-warfarin and theratio of the C_(max) for co-administered R-warfarin and/or S-warfarinafter implantation of the implantable delivery device and duringcontinuous subcutaneous dosing of the GLP-1 analog relative to referenceC_(max) for R-warfarin and/or S-warfarin administered alone is less than1.5 or 1.25.

In some embodiments, the drug is co-administered without doseadjustment. In other words, the normally prescribed dose for the drug isnot changed after implantation of the delivery device and duringcontinuous subcutaneous dosing of the GLP-1 analog.

In some embodiments, the drug is self-administered by the subject. Inother words, the drug, either prescribed by a physician or obtained asan over-the-counter drug, is taken orally by the subject.

In another aspect, the present invention provides a method comprisingadministering to a subject, via an implantable delivery device, acontinuous subcutaneous dose of glucagon-like peptide-1 (GLP-1) analog,without providing a substantial delay in a rate of gastric emptying inthe subject, following administration, relative to the rate of gastricemptying for the subject prior to administration.

In another aspect, the present invention provides a drug for use in amethod of treatment of a subject (e.g., a patient suffering from T2Dand/or obesity and/or in need of weight loss), the method comprisingadministering to the subject (e.g., patient), via an implantable osmoticdelivery device, a continuous subcutaneous dose of a glucagon-likepeptide-1 (GLP-1) analog without providing a substantial delay in a rateof gastric emptying in the subject, following administration, relativeto the rate of gastric emptying for the subject prior to administration.

In some embodiments, the method provides less than 20% delay in the rateof gastric emptying in the subject, following administration, relativeto the rate of gastric emptying for the subject prior to administration.In some embodiments, the method provides less than 10%, 5% or 1% delayin the rate of gastric emptying in the subject, followingadministration, relative to the rate of gastric emptying for the subjectprior to administration.

In some embodiments, the method provides no substantial delay in therate of gastric emptying in the subject, between 5 and 29 days followingadministration, relative to the rate of gastric emptying for the subjectprior to administration. In some embodiments, the method provides nosubstantial delay in a rate of gastric emptying in the subject, between1 day and 1 week, between 1 day and 2 weeks, or between 1 day and 1month, following administration, relative to the rate of gastricemptying for the subject prior to administration. In some embodiments,the method provides no substantial delay in a rate of gastric emptyingin the subject, during continuous subcutaneous delivery (e.g., duringthree, six, twelve, or twenty-four month administration period) of aGLP-1 analog such as exenatide (e.g. ITCA-650 at 20 μg/day exenatide orITCA-650 60 μg/day exenatide).

In some embodiments, the method provides no substantial delay in thefasting rate of gastric emptying. Fasting conditions (e.g., those withina fasting period of at least 24, 12, 8, 6, 4 or 2 hours withoutconsumption of food or a meal) correspond to those well known to thoseof ordinary skill in the art. As used herein, the term “substantial”corresponds to less than 20%, less than 10%, less than 5% or less than1%.

In some embodiments, the method provides no substantial (e.g., less than20%, less than 10%, less than 5% or less than 1%) delay in thepost-prandial rate of gastric emptying. Post-prandial conditions (e.g.,those within a feeding period of 12, 8, 6, 4, 2 or 1 hour(s), duringwhich food or a meal was consumed) correspond to those well known tothose of ordinary skill in the art.

In another aspect, the present invention provides a method comprisingadministering to a subject, via an implantable delivery device, acontinuous subcutaneous dose of glucagon-like peptide-1 (GLP-1) analogwithout effecting a substantial reduction in glucagon concentration inblood of the subject, following administration, relative to glucagonconcentration in blood of the subject prior to administration.

In another aspect, the present invention provides a drug for use in amethod of treatment of a subject (e.g., a patient suffering from T2Dand/or obesity and/or in need of weight loss), the method comprisingadministering to the subject (e.g., patient), via an implantable osmoticdelivery device, a continuous subcutaneous dose of a glucagon-likepeptide-1 (GLP-1) analog without providing a substantial reduction inglucagon concentration in blood of the subject, followingadministration, relative to glucagon concentration in blood of thesubject prior to administration.

In some embodiments, the method provides less than 20% reduction inglucagon concentration in blood of the subject, followingadministration, relative to glucagon concentration in blood of thesubject prior to administration. In some embodiments, the methodprovides less than 10%, 5% or 1% reduction in glucagon concentration inblood of the subject, following administration, relative to glucagonconcentration in blood of the subject prior to administration.

In some embodiments, the method provides no substantial reduction inglucagon concentration in blood of the subject, between 5 and 29 daysfollowing administration, relative to glucagon concentration in blood ofthe subject prior to administration. In some embodiments, the methodprovides no substantial reduction in glucagon concentration in blood ofthe subject, between 1 day and 1 week, between 1 day and 2 weeks, orbetween 1 day and 1 month, following administration, relative toglucagon concentration in blood of the subject prior to administration.In some embodiments, the method provides no substantial reduction inglucagon concentration in blood of the subject, during continuoussubcutaneous delivery (e.g., during three, six, twelve, or twenty-fourmonth administration period) of a GLP-1 analog such as exenatide (e.g.ITCA-650 at 20 μg/day exenatide or ITCA-650 60 μg/day exenatide).

In some embodiments, the method provides no substantial (e.g., less than20%, less than 10%, less than 5% or less than 1%) reduction in fastingglucagon concentration.

In some embodiments, the method provides no substantial (e.g., less than20%, less than 10%, less than 5% or less than 1%) reduction inpost-prandial glucagon concentration.

In some embodiments, the GLP-1 analog is exenatide. In some embodiments,the GLP-1 analog is other than exenatide. In some embodiments, the GLP-1analog is selected from the group consisting of Ozempic® (semaglutide),Victoza® (liraglutide), Adlyxin® (lixisenatide), Tanzeum® (albiglutide),and Trulicity® (dulaglutide). In some embodiments, the GLP-1 analog isOzempic® (semaglutide). In some embodiments, the GLP-1 analog isVictoza® (liraglutide). In some embodiments, the GLP-1 analog isAdlyxin® (lixisenatide). In some embodiments, the GLP-1 analog isTrulicity® (dulaglutide). In some embodiments, the GLP-1 analog isTanzeum® (albiglutide).

In some embodiments, the GLP-1 analog is administered for treatment of ametabolic disorder. In some embodiments, the GLP-1 analog isadministered for treatment of a type 2 diabetes mellitus. In someembodiments, the GLP-1 analog is administered for treatment of obesity.In some embodiments, the GLP-1 analog is administered for effectingweight loss in the subject.

In some embodiments, the subject is administered a dose of 20 μg/dayITCA-650. In some embodiments, the subject is administered a dose of 60μg/day ITCA-650.

In some embodiments, the subject is human.

EXEMPLIFICATION

The following examples are put forth to provide those of ordinary skillin the art with a complete disclosure and description of how to practicethe present invention, and are not intended to limit the scope of whatthe inventors regard as the invention. Efforts have been made to ensureaccuracy with respect to numbers used (e.g., amounts, concentrations,and percent changes) but some experimental errors and deviations mayremain.

General Methods for Examples 1-3

Data source: Data relating to the Meal Tolerance Test (MTT) were derivedfrom the evaluable cohort, comprising all randomized subjects whocompleted Day −1 (pre-treatment) MTT assessments and completed allpharmacodynamic assessments for at least one of the three scheduledpost-treatment MTT assessments. One subject from the originallyrandomized cohort of n=45 that completed pre-treatment MTT did notcomplete any post-treatment MTT assessments and was excluded from theevaluable cohort. Thus, there were 44 subjects in the evaluablepopulation: 12 subjects in the ITCA 650 10 mcg/day group, 11 subjects inthe ITCA 650 20 mcg/day group, 10 subjects in the ITCA 650 40 mcg/daygroup, and 11 subjects in the ITCA 650 80 mcg/day group. Of allscheduled MTT assessments, 43/44 (98%) were completed on Day 5, 37/44(84%) on Day 15, and 42/44 (95%) on Day 29.

Data from SAS dataset “LB” containing all lab values were downloadedinto an Excel file (2013 v15 Office 365 module) for sorting of plasmaglucose, insulin and glucagon values by treatment group, subject, visitnumber, and time within the meal tolerance assessment (there being 7values, including 1 pre-meal and 6 post-meal, for each analyte).Assembled Excel tables were imported into GraphPad Prism (v7.02.185,www.graphpad.com, San Diego, Calif.) for graphical analysis.

Values missing from a time series, where there was a preceding andfollowing value, were imputed by linear interpolation. Where an initialvalue in a time series was missing, it was imputed as the median of thevalues present at that time point. Since initial values were typicallylow, the bias from this treatment is likely negligible. The number ofvalues imputed by this method was 11 (of a final matrix of 3611 values;0.3%).

Example 1. ITCA-650 and Gastric Emptying Rate

Changes in plasma glucose result from differences in rate of appearance(Ra) and rate of disappearance (Rd; disposal). Rd is primarily aninsulin-driven flux. Ra is comprised of meal-related appearance, as wellas glucose from endogenous sources, such as hepatic gluconeogenesis.Because insulin is initially low, and takes time to reach its cellulartarget in the fat and muscle interstitium, and because it takes time toexert its cellular effect of mobilizing GLUT4 transporters, most of themeal-related changes in the initial 30-60 minutes after a meal relate torates of appearance. Agents that slow the emptying of the stomach,including amylin agonists, CCK agonists, PYY agonists and GLP-1agonists, dose-dependently suppress glucose rise following test meals,regardless of the effect of such agents to modify insulin secretion.When glucose is the test meal (OGTT), simultaneously measured gastricemptying correlated highly with changes in plasma glucose at 30 min(Horowitz, M., M. A. Edelbroek, J. M. Wishart and J. W. Straathof(1993). “Relationship between oral glucose tolerance and gastricemptying in normal healthy subjects.” Diabetologia 36(9): 857-862).Changes in plasma glucose from pre-meal to 30 minutes post-meal(ΔGlucose₃₀) were explored as evidence of an effect of ITCA-650 ongastric emptying.

Methods

Changes (ΔGlucose₃₀) were related to those observed before treatment,and the difference (ΔΔGlucose₃₀) explored as a function of duration oftreatment and exenatide infusion rate. Dose responses were fitted to a3-parameter sigmoid (GraphPad Prism v7; www.graphpad.com; San DiegoCalif.), and the fits constrained so that the dose-responses from eachof the 3 durations of treatment (5, 15 and 29 days) shared a commonED₅₀.

Results

The ΔGlucose₃₀ for each dose group, before and after 5, 15 and 29 daysof treatment are shown in FIG. 1 which illustrates 0-30-minuteincrements in plasma glucose during test meals for 10-, 20-, 40- and 80μg/day exenatide treatments, measured before and after 5, 15, and 29days of treatment. Symbols are group means of individualincrements±standard error of the mean (SEM).

The ΔΔGlucose₃₀, representing the pretreatment-referenced change, isplotted as a function of dose in FIG. 2. A dose-dependency of ΔGlucose₃₀was suggested after 15 days of treatment (r² 0.22), but this was notapparent either before, at Day 5 (r² 0.02) or after, at Day 29 (r²0.01).

FIG. 2 illustrates dose-responses for 30-minute changes in glucoseconcentrations during test meals relative to pre-treatment values.Curves for Days 5, 15 and 29 are 3-parameter sigmoids constrained toshare a common ED₅₀. Symbols are group means of individual values±SEM.

Exemplary Conclusions

Changes in plasma glucose after a test meal, as shown in FIG. 1, were ofthe order of 40 to 60 mg/dL 30 minutes after the meal. The incrementsafter treatment were similar to the values recorded in the same subjectsprior to treatment.

A dose-dependency of changes relative to those observed prior totreatment was suggested after 15 days of treatment, but was not presentafter either 5 or 29 days of treatment.

The magnitude of suppression of post-meal glucose increments, wherepresent, was small compared to another study in non-diabetic subjectswhere changes in post-meal glucose were measured following s.c. bolusinjections of 5 or 19 μg exenatide (Linnebjerg, H., P. A. Kothare, Z.Skrivanek, A. de la Pena, C. Ernest, M. Atkins and M. E. Trautmann(2004). “Exenatide: postprandial glucose pharmacodynamics at variousdosing times relative to a meal in patients with type 2 diabetes.”Diabetologia 47(suppl 1): A280. Abstract 776). The exenatidedose-dependency observed in that study, and in another where glucose wasthe test meal (OGTT) (Kolterman, O. G., J. B. Buse, M. S. Fineman, E.Gaines, S. Heintz, T. A. Bicsak, K. Taylor, D. Kim, M. Aisporna, Y. Wangand A. D. Baron (2003). “Synthetic exendin-4 (exenatide) significantlyreduces postprandial and fasting plasma glucose in subjects with type 2diabetes.” J Clin Endocrinol Metab 88(7): 3082-3089) was not aconsistent feature in the current study.

Without being bound by theory, it thus appears that the effect of bolusinjections of exenatide on post-prandial glucose changes may be, atleast in part, a consequence of inhibition of gastric emptying. Bycontrast, gastric emptying does not appear to be inhibited upon chronicinfusion of exenatide, as in the present study.

Example 2. ITCA-650 and Post-Prandial Glucagon Secretion

Exaggeration of glucagon secretion in response to protein-containingmeals has been reported in subjects with insulinopenic diabetes,including severe type 2 diabetes (Raskin, P., I. Aydin, T. Yamamoto andR. H. Unger (1978). “Abnormal alpha cell function in human diabetes: theresponse to oral protein.” Am J Med 64(6): 988-997) and has beenimplicated in the pathogenesis of disturbed metabolism (Unger, R. H.(1978). “Role of glucagon in the pathogenesis of diabetes: the status ofthe controversy.” Metabolism 27(11): 1691-1709).

Methods

Plasma glucagon concentration profiles during meal tolerance tests wereplotted as a function of treatment (10-, 20-, 40- and 80-μg exenatideper day) and as a function of duration of treatment (pre-treatment andafter 5, 15 and 29 days of treatment). Means and SEM of the data at eachof these 16 conditions (4 treatments×4 durations) was derived from datapresent with no imputation of missing values. Numbers of values presentranged from 7-12.

Data were also analyzed as absolute change from baseline (Δglucagon),and plotted as for glucagon for each of the 16 conditions.

Area under the curve for total glucagon (AUC₀₋₃) and for change inglucagon from 0 min during the MTT (ΔAUC₀₋₃) were derived by trapezoidalinterpolation and were each plotted as a function of duration oftreatment for each of the treatment groups.

Results

Plasma glucagon profiles during meal tolerance tests are plotted as afunction of duration of treatment, for each dose group in separatepanels, in FIG. 3. Plasma glucagon profiles were typically maximal 30min after the test meal, declining gradually thereafter. The profileswere similar between all 16 treatments shown. A high initial baselineand high SEM in the 80-μg/day treatment group at Day 29 was driven by 2subjects with values 4- to 6-fold higher than values in the other 15treatment conditions, and may not be reliable.

FIG. 3 illustrates plasma glucagon profiles during meal tolerance testsplotted according to duration of treatment (different symbols andcolors) for each of the 4 dose groups (separate panels). Symbols aremeans±SEM for data present at each condition.

Change in plasma glucagon from pre-meal values is plotted in FIG. 4.Profiles were generally similar for each of the 16 conditions. Whilechanges appeared less for 40- and 80-μg/day treatments at Day 29, therewas no indication of a suppression of post-prandial glucagon at Day 15.These measures may be unreliable for the reasons addressed above.

FIG. 4 illustrates changes in plasma glucagon concentration frompre-meal values during a test meal. Symbols, colors and layout have thesame meanings as those in FIG. 3.

The AUC for absolute glucagon concentrations and for post-meal change inconcentration graphed in FIGS. 3 and 4, are plotted in FIG. 5 as afunction of duration of treatment for each of the 4 dose groups.

By neither analysis does there appear to be a change from pre-treatmentAUC₀₋₃ or ΔAUC₀₋₃ at any duration of treatment.

FIG. 5 illustrates integrated glucagon concentrations (left panel) orglucagon changes (right panel) during Meal Tolerance Test (MTT) as afunction of duration of treatment for each dose group.

Exemplary Conclusions

The data obtained for continuous subcutaneous infusions of exenatidewith ITCA-650 do not support suppression of post-prandial glucagon as asignificant mechanism underlying its glucose-lowering effect. Theseobservations contrast with those of Kolterman et al. (Kolterman, et al.,J Clin Endocrinol Metab 2003) where bolus subcutaneous injections of1-μg/kg exenatide abrogated the ˜70 pg/mL increase in plasma glucagon 1hour after a test meal. Since meal-stimulated glucagon secretion may beat least partially moderated by changes in gastric emptying, the absenceof effect here may be consistent with an absence of effect ofcontinuously delivered exenatide on gastric emptying, as describedabove.

Example 3. ITCA-650 and Glucose-Stimulated Insulin Secretion

The ability of glucagon-like peptide-1 was reported in 1987 (Mojsov, S.,G. C. Weir and J. F. Habener (1987). “Insulinotropin: glucagon-likepeptide I (7-37) co-encoded in the glucagon gene is a potent stimulatorof insulin release in the perfused rat pancreas.” J Clin Invest 79(2):616-619) to stimulate insulin secretion in a glucose-dependent manner,having no effect at low plasma glucose concentrations. Every GLP-1agonist reported since then appears to have this property. We thereforesought to determine whether the relationship between resulting plasmainsulin concentrations and simultaneously determined plasma glucoseconcentrations in the present study supported such a mechanism.

A challenge arises in determining the [insulin]/[glucose] relationshipin subjects with type 2 diabetes because the natural history of T2Dplaces subjects in different zones of the [insulin]*[glucose] plane,according to the stage of their disease. Proposed by Reaven and Miller(Reaven, G. M. and R. Miller (1968). “Study of the relationship betweenglucose and insulin responses to an oral glucose load in man.” Diabetes17(9): 560-569) based upon cross-sectional data, and affirmed by Saad etal. (Saad, M. F., W. C. Knowler, D. J. Pettitt, R. G. Nelson, D. M. Mottand P. H. Bennett (1989). “Sequential changes in serum insulinconcentration during development of non-insulin-dependent diabetes.”Lancet 1(8651): 1356-1359) based upon longitudinal data, the progressionbegins with amplification of insulin secretion, accompanied by moderatedysglycemia, as insulin resistance becomes established. This is followedin a subset of individuals by florid hyperglycemia, as insulin secretorycapacity fails, likely due to islet destruction by amyloid. The resultis an inverted U-shaped distribution of [insulin]/[glucose] data pairs,shown for the 2-hour post-OGTT timepoint in FIG. 6A. Individuals tend tofollow the trajectories of the yellow arrows as they progress fromnormal, to IGT, to T2D. FIG. 6B, shows [insulin]/[glucose] diagrams fromthe MTT in T2D subjects prior to treatment with 80-μg/day exenatide. Theprogression mapped in FIG. 6A is apparent in the [insulin/[glucose]diagram from the current study in FIG. 6B. The sequence of serialmeasurements is indicated by the direction of the arrows. For example,subjects 31-047 and 31-044 show a vigorous insulin response with modestincreases in glucose following the test meal, consistent with theinsulin resistant phase of progression. In contrast, subjects 32-021 and33-026 show large glycemic excursions and only meager insulin responses,consistent with the secretory failure phase of disease progression.Another feature of the [insulin]/[glucose] trajectories in the currentstudy is hysteresis, wherein the path of descending data pairs isdifferent from that of ascending data pairs. Accommodation of thesefeatures is addressed in the analytic methods.

FIG. 6A (left), redrawn from Saad et al., maps the changing [insulin] vs[glucose] relationship during the progression from normal glucosetolerance to T2D. FIG. 6B (right) exemplifies the diverse [insulin] vs[glucose] relationships in the current study.

Methods

The effect of glucose upon insulin secretion was quantified as the slopeof the [insulin] vs [glucose] relationship, as exemplified in FIG. 6B.The slope was estimated by linear regression, the intersection with theX-axis being unique for each subject.

Because of factors such as the time lag for induction of insulin effect,and non-instantaneous clearance of secreted insulin, only data pairs forthe ascending part of the hysteresis loop were used in the analysis.These segments are signified by the thick lines in FIG. 6B. Thus,subjects 31-044 and 31-047 yielded similar slopes. Subjects 32-021 and32-032 had similar slopes but different intersections with the X-axis.Subject 33-026 had the lowest slope.

Such diagrams were analyzed for each subject for each meal tolerancetest (pre-treatment and after 5, 15 and 29 days of treatment).Observation suggested that the X-intercept (glucose concentration belowwhich insulin was not secreted) was essentially unchanged by thetreatments, so linear regression was constrained to yield a best-fittingfixed X-intercept for all tests in a given subject. Families of up to 4[insulin] vs [glucose] relationships were fitted to a straight linewhere the X-intercept was shared, but slopes were able to vary. This wasdone by fitting the equation [glucose]=m. [insulin]+c (actually theinverse of slopes in FIG. 6B) using least squares interaction in thenon-linear module of Prism v7 (www.graphpad.com; San Diego, Calif.), andretrieving the reciprocal of m as the [insulin] vs [glucose] slope.

Because pre-treatment slopes varied widely between individuals, slopesderived during treatment were expressed as a multiple of thepre-treatment slope. Negative slopes, comprising 4/216 (1.8%) of thosederived, were disregarded.

Results

The slope of the [insulin]/[glucose] relationship increased from1.7-fold with 10 μg/day treatment up to 3.45-fold with 80 μg/daytreatment. The slope was near maximal after a week (tau 3.5 days), asshown in FIG. 7.

FIG. 7 illustrates multiples above pre-treatment baseline of bestfitting [insulin]×[glucose] slopes. The curves are the best fittingexponential association as a function of duration of treatment.

The relative increments in slope after 29 days were analyzed by dosegroup to obtain the dose response relationship shown in FIG. 8. Thesigmoid fit suggests the ED₅₀ for the slope change is −40 μg/day.

FIG. 8 illustrates dose response for the effect of ITCA-650 to increaseslope of the [insulin]/[glucose] relationship.

Exemplary Conclusions

Analysis of treatment-related changes in [insulin] vs [glucose]relationships during meal tolerance tests are indicative of aninsulinotropic effect of ITCA-650. Dose response analysis indicates thiseffect is dose dependent, and that the ED₅₀ may be near or belowindicated doses.

Example 4. ITCA 650 and the Pharmacokinetics (PK) of Acetaminophen(APAP) and Other Commonly Co-Administered Drugs

Methods

Thirty-three (33) healthy volunteers were enrolled in a sequential,open-label study to assess the effect of ITCA 650 on the PK of APAP 1000mg, and on the PK and pharmacodynamics (PD) of 4 commonlyco-administered drugs: atorvastatin (40 mg), lisinopril (20 mg), digoxin(0.5 mg), and warfarin (25 mg) administered as a cocktail. See FIG. 9.APAP, a marker of gastric emptying, was administered on Day (D)1followed by the cocktail on D2. ITCA 650 20 mcg/day was placed on D6 andreplaced by ITCA 650 60 mcg/day on D20. APAP was administered again onD27 and the cocktail on D28. ITCA 650 60 mcg/day was removed on D32.Serial PK (exenatide; co-administered drugs) and PD (PT-INR) sampleswere collected.

Results

There was minimal effect of ITCA 650 on gastric emptying rate as seen inFIG. 9 with the 90% CI of the LS means ratio for AUC between 80-125%.There were no changes in digoxin and warfarin PK or INR. While therewere moderate increases in lisinopril and atorvastatin exposures, therewere no clinically relevant effects on safety and tolerability of eitherdrug.

Exemplary Conclusion

There was no substantial effect of ITCA 650 on gastric emptying and nodosage adjustment is deemed necessary when ITCA 650 is co-administeredwith these commonly used drugs.

Example 5. ITCA 650 and the PK and Pharmacodynamics (PD) of aCombination Oral Contraceptive (OC)

Methods

Twenty-eight (28) healthy premenopausal women on a stable regimen of anOC participated in a randomized, double-blind, placebo-controlled,2-period crossover study. The effect of ITCA 650 on the steady-state PKof ethinyl estradiol (EE) and levonorgestrel (LNG) from Levora® (OC)were evaluated. The study included a 2-week run-in on Levora and 2treatment periods of 28 days each. In Period 1, ITCA 650 20 mcg/day orITCA placebo was placed on Day (D) 1 followed by removal and replacementwith ITCA 650 60 mcg/day or ITCA placebo on D15. Subjects were crossedover to the alternative treatment and procedures were repeated in Period2. The OC was administered daily through D28 of each period. Serialsamples for PK analysis of exenatide, EE, LNG, and pharmacodynamics (LH,FSH, and progesterone) analysis were collected.

Results

No effect of ITCA 650 60 mcg/day on EE and LNG PK was observed (FIG.10). The 90% CIs of the geometric LS mean treatment ratios for AUC_(ss)and C_(max,ss) were contained within the equivalence limits of 80% to125%. Levels of LH, FSH, and progesterone were unaffected by theadministration of ITCA 650.

Exemplary Conclusion

No dose adjustments are required when ITCA 650 is administered withLevora, a combination OC.

Example 6. Drug Interaction Studies—Potential for Exenatide to Influencethe Pharmacokinetics of Other Drugs

In clinical pharmacology studies ITCA-650 did not affect thepharmacokinetics of the orally administered medications to a clinicallyrelevant degree. FIG. 11 illustrates pharmacokinetic parameters andtheir 90% confidence intervals (CI), indicating the magnitude of theseinteractions. No dose adjustment is recommended for any of the evaluatedco-administered medications. ITCA-650 had a minimal effect onacetaminophen pharmacokinetics indicating that it has a minimal effecton gastric emptying. ITCA-650 did not significantly alter thepharmacodynamic effects of warfarin as measured by the internationalnormalized ratio (INR).

We claim:
 1. A method comprising administering to a subject in needthereof, via an implantable delivery device, a continuous subcutaneousdose of glucagon-like peptide-1 (GLP-1) analog, wherein the subject isorally co-administered a drug after implantation of the implantabledelivery device and during continuous subcutaneous dosing of the GLP-1analog, and wherein the drug is administered without dose adjustment fortreatment of a disease or disorder other than type-2 diabetes.
 2. Themethod of claim 1, wherein the disease or disorder other than type-2diabetes is selected from the group consisting of pain, elevated bloodlevels of cholesterol, heart disease, hypertension, heart attack, strokeor blood clot.
 3. The method of claim 1, wherein the drug isadministered to prevent conception of a child.
 4. The method of claim 1,wherein the drug is selected from the group consisting of acetaminophen,atorvastatin, lisinopril, digoxin, ethinyl estradiol, andlevonorgestrel, R-warfarin, and S-warfarin.
 5. The method of claim 1,wherein the drug is a pain reliever.
 6. The method of claim 1, whereinthe drug is acetaminophen.
 7. The method of claim 1, wherein the drug isan oral contraceptive.
 8. The method of claim 1, wherein the drug is oneor both of ethinyl estradiol and levonorgestrel.
 9. The method of claim1, wherein the drug is for the treatment of elevated blood levels ofcholesterol.
 10. The method of claim 1, wherein the drug is a statin.11. The method of claim 1, wherein the drug is atorvastatin.
 12. Themethod of claim 1, wherein the drug is for the treatment or preventionof hypertension and/or heart disease.
 13. The method of claim 1, whereinthe drug is digoxin.
 14. The method of claim 1, wherein the drug is anangiotensin converting enzyme (ACE) inhibitor.
 15. The method of claim1, wherein the drug is lisinopril.
 16. The method of claim 1, whereinthe drug is for the treatment or prevention of a heart attack, stroke,hypertension or blood clot.
 17. The method of claim 1, wherein the drugis an anticoagulant.
 18. The method of claim 1, wherein the drug isR-warfarin and/or S-warfarin.
 19. The method of claim 1, wherein thedrug is self-administered by the subject.
 20. The method of claim 1,wherein the GLP-1 analog is exenatide.
 21. The method of claim 1,wherein the GLP-1 analog is other than exenatide.
 22. The method ofclaim 21, wherein the GLP-1 analog is selected from the group consistingof OZEMPIC® (semaglutide), VICTOZA® (liraglutide), ADLYXIN®(lixisenatide); TENZEUM® (albiglutide) and TRULICITY® (dulaglutide). 23.The method of claim 1, wherein the GLP-1 analog is administered fortreatment of a metabolic disorder.
 24. The method of claim 1, whereinthe GLP-1 analog is administered for treatment of a type 2 diabetesmellitus.
 25. The method of claim 1, wherein the GLP-1 analog isadministered for treatment of obesity.
 26. The method of claim 1,wherein the GLP-1 analog is administered for effecting weight loss inthe subject.
 27. The method of claim 1, wherein the subject isadministered a dose of 20 μg/day exenatide.
 28. The method of claim 1,wherein the subject is administered a dose of 60 μg/day exenatide. 29.The method of claim 1, wherein the subject is human.